This is a competing continuation for a grant entitled Biomarkers of Cognitive Decline among Normal Individuals: The BIOCARD Cohort' (see FOA: PAR-13-148). The BIOCARD study is a longitudinal, observational study of 349 individuals who were cognitively normal and primarily middle aged (mean age=57.1) at enrollment. By design, more than two-thirds had a family history of Alzheimer's disease (AD). The primary goal was to follow individuals from normal cognition to mild cognitive impairment (MCI) or dementia, so that it would be possible to identify biomarkers that predicted progression. The rationale for this study design is that several lines of evidence indicate that AD pathophysiological processes begin to develop many years, if not decades, before AD dementia is diagnosed. This long prodromal phase provides a 'window of opportunity' during which symptoms are minimal (if present at all) but therapeutic intervention may have the greatest opportunity of success. The BIOCARD study is in a unique position to examine 'preclinical AD', since the participants: (1) have been followed for up to 18 years (mean follow-up = 12.1 yrs), (2) are entering a period of accelerating risk, and (3) 63 of those alive have developed mild cognitive impairment (MCI) or dementia. Our overall objectives are to further advance the study of preclinical AD by: (1) clarifying the pattern and rate of changes in AD biomarkers (including CSF, MRI, amyloid imaging and blood) and cognition that occur, as well as evaluate potential new biomarkers, (2) maximizing our data by working collaboratively with several research groups who have comparable data, and (3) providing a publicly accessible database, to include biological specimens, for researchers in the field. The long duration of follow-up for the cohort is based on the fact that the study was established in 1995 by investigators in the intramural program of the NIH. The study was stopped for administrative purposes in 2005. Our investigative team was funded in July 2009 to re-enroll the participants and re-initiate longitudinal data collection. Wit this application, we are requesting funds to continue the longitudinal clinical and cognitive assessment of the cohort, collect more CSF, more MRI scans, and to initiate acquisition of positron emission tomography (PET), using [11-C] PiB, in the participants who remain cognitively normal (n=201). Though a number of studies around the world have begun to examine cognitively normal individuals with similar goals in mind, no study, to our knowledge, has up to 18 years of accumulated longitudinal data on changes in cognitive, CSF, and MRI measures first obtained when the subjects were cognitively normal and the majority were middle aged.